I am a principal investigator with 15 years of training and research in Alzheimer's disease and neurodegeneration. The long-term goals for my research career are to 1) clearly understand the molecular and cellular mechanisms that drive the accumulation of amyloid beta protein in Alzheimer's disease, 2) mechanistically define signaling pathways that mediate and/or potentiate the deleterious effects of pathological lesions in neurodegenerative diseases, and 3) identify novel therapeutic targets and approaches to treat neurodegeneration. Using a yeast 2-hybrid screen, we recently identified 2 new proteins, RanBP9 and Snapin, which interact with a previously uncharacterized domain of LRP cytoplasmic tail (CST) and modulate APP processing. Our working hypothesis is that the LRP-C37 domain and its interacting proteins, in particular RanBP9, play important roles in APP trafficking and Abeta generation. My short-term goals relevant for this K02 application relate to the role of the LRP/RanBP9 pathway in the regulation of APP/Abeta metabolism. Specifically, they are to 1) determine the mechanistic basis of LRP-C37 domain of LRP in APP trafficking and Abeta generation, 2) study the role of Snapin and RanBP9 in LRP / APP trafficking and Abeta production in cultured cells and in vivo, and 3) identify peptide sequences potentially capable of blocking the pro-amyloidogenic action of RanBP9 by phage display screening. In addition, I would like to take this opportunity to significantly further my repertoire of research techniques by taking the time to attend training courses and initiate collaborations with experts in research techniques I aspire to learn, especially in sophisticated imaging techniques, embryological, and advanced neuroscience techniques. These research tools will not only complement the currently funded research proposed here but will also help to solve future research challenges in the next phase of my career. RELEVANCE: As the major defining characteristic of Alzheimer's disease (AD) brains is the excessive accumulation of a toxic protein called Abeta, understanding the biological mechanisms by which Abeta is generated is critical for designing effective therapeutic strategies for AD. This proposal is aimed at providing a novel approach for therapeutically targeting Abeta in AD by characterizing the LRP / RanBP9 pathway.